Gut microbial GABAergic signaling imprints alveolar macrophages and pulmonary response to viral infection associated with psychological stress

Abstract Background Epidemiological evidences reveal that populations with psychological stress have an increased likelihood of respiratory viral infection involving influenza A virus (IAV) and SARS-CoV-2, but the mechanism remains elusive. Results By exploiting a chronic restraint stress (CRS) mouse model, we demonstrated that psychiatric stress substantially increased hosts’ vulnerability to viral pneumonia, concurrent with deregulated alveolar macrophages (AMs) and disturbed gut microbiome. The central importance of gut microbiome in stress-exacerbated viral pneumonia was confirmed by microbiome depletion and gut microbiome transplantation. In particular, stress exposure induced a decline in Lactobacillaceae abundance and hence γ-aminobutyric acid (GABA) level in mice. Microbial-derived GABA proved to be released in the peripheral and sensed by AMs via GABAAR, leading to enhanced mitochondrial metabolism and α-ketoglutarate (αKG) generation. The metabolic intermediator in turn served as the cofactor for the epigenetic regulator Tet2 to catalyze DNA hydroxymethylation, and promoted PPARγ-centered gene program underpinning survival, self-renewing, and immunoregulation of AMs. We thus uncover an unappreciated GABA/Tet2/PPARγ regulatory circuitry that was initiated by gut microbiome to instruct distant immune cells through a metabolic-epigenetic program. Accordingly, reconstitution with GABA-producing probiotics, or adoptive transferring of GABA-conditioned AMs, or resumption of pulmonary αKG level remarkably improved AMs homeostasis and alleviated severe pneumonia in stressed mice. Conclusions Together, our study identifies a microbiome-derived tonic signaling that is tuned by mental health status to imprint resident immune cells and defensive response in lungs. The findings are particularly significant for the subpopulation with psychiatric stress to combat critical respiratory viral infection.